Oncogene (2014) 33, 939–953 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc

REVIEW The regulatory roles of phosphatases in cancer

J Stebbing1, LC Lit1, H Zhang, RS Darrington, O Melaiu, B Rudraraju and G Giamas

The relevance of potentially reversible post-translational modifications required for controlling cellular processes in cancer is one of the most thriving arenas of cellular and molecular biology. Any alteration in the balanced equilibrium between kinases and phosphatases may result in development and progression of various diseases, including different types of cancer, though phosphatases are relatively under-studied. Loss of phosphatases such as PTEN (phosphatase and tensin homologue deleted on chromosome 10), a known tumour suppressor, across tumour types lends credence to the development of phosphatidylinositol 3--kinase inhibitors alongside the use of phosphatase expression as a biomarker, though phase 3 trial data are lacking. In this review, we give an updated report on phosphatase dysregulation linked to organ-specific malignancies.

Oncogene (2014) 33, 939–953; doi:10.1038/onc.2013.80; published online 18 March 2013 Keywords: cancer; phosphatases; solid tumours

GASTROINTESTINAL MALIGNANCIES abs in sera were significantly associated with poor survival in Oesophageal cancer advanced ESCC, suggesting that they may have a clinical utility in Loss of PTEN (phosphatase and tensin homologue deleted on ESCC screening and diagnosis.5 chromosome 10) expression in oesophageal cancer is frequent, Cao et al.6 investigated the role of protein tyrosine phosphatase, among other gene alterations characterizing this disease. Zhou non-receptor type 12 (PTPN12) in ESCC and showed that PTPN12 et al.1 found that overexpression of PTEN suppresses growth and protein expression is higher in normal para-cancerous tissues than induces apoptosis in oesophageal cancer cell lines, through in 20 ESCC tissues. By performing IHC, high and low expression of downregulation of BCL2 resulting in changes in cell-cycle PTPN12 was found in 62.1% and 37.9% of ESCCs, respectively. progression. Moreover, they have shown that PTEN gene therapy Moreover, they demonstrated that patients with completely reduces tumour size in vivo, suggesting PTEN as an important resected ESCC and tumours with high PTPN12 expression biological marker. In addition, Hou et al.2 investigated the tumour had favourable survival compared with that of patients relationship of PTEN status and cell sensitivity to chemo- with low PTPN12, therefore proposing that PTPN12 can be used as therapeutic drugs in vivo. Esophageal squamous cell carcinoma an independent predictor of patient survival.6 (ESCC) cells transfected with or without the wild-type PTEN were You et al.7 evaluated the methylation levels of protein tyrosine inoculated subcutaneously into nude mice. Both wild-type PTEN phosphatase receptor type O (PTPRO) promoter as a potential and cisplatin could inhibit tumour growth and induce cell biomarker in ESCC. Their analysis revealed hypermethylated apoptosis. Cisplatin had the strongest inhibitory effects on PTPRO promoter status in 27 (75%) out of 36 primary tumours. tumours produced by cells transfected with wild-type PTEN, No methylated PTPRO was observed in normal peripheral blood indicating that PTEN can increase the in vivo sensitivity of ESCC samples from 10 healthy individuals. In addition, in PTPRO- cells to cisplatin. As further evidence of the importance of PTEN in silenced cell lines, expression was dramatically restored by oesophageal carcinogenesis, Ma et al.3 have recently found a treatment with the demethylating agent 5-azadC, confirming strong association of genetic polymorphisms in PTEN with high that DNA methylation is a mechanism regulating PTPRO risk of ESCC. expression and that aberrant methylation of the PTPRO In another study, immunohistochemistry (IHC) of 100 patients’ promoter is directly responsible for transcriptional inactivation of tumours with ESCC revealed that cell division cycle 25 homologue its expression in ESCC cell lines. These findings suggest that PTPRO A (CDC25A) and CDC25B phosphatases are strongly expressed in is a common target for epigenetic silencing via methylation in the cytoplasm of cancer cells.4 Furthermore, due to the role of ESCC and that its methylation may be involved in oesophageal CDC25B in cell growth, Dong et al.5 examined the levels of cancer tumourigenesis.7 Moreover, Motiwala et al.8 examined the CDC25B antibodies (abs) in sera from 134 oesophageal squamous levels of PTPRO methylation in blood cells, as the presence of cell carcinoma patients and determined that they are higher detectable methylated promoter DNA in blood cells has been compared with healthy subjects. Detection of CDC25B abs in reported to indicate the presence of circulating cancer cells during combination with traditional tumour markers (that is, the process of distant metastasis. Interestingly, PTPRO methylation carcinoembryonic antigen, squamous cell carcinoma antigen, occurred only in B-cell population of a subset of patients with cytokeratin fragment 21-1 (CYFRA21-1)) resulted in an increased chronic lymphocytic leukaemia, but not in normal B or sensitivity of detection, with 64.2% of patients testing positive for T lymphocytes, indicating that methylated PTPRO in blood cells at least one of these markers. Moreover, high levels of CDC25B is cancer-specific.8 Finally, a high frequency of PTPRO

Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK. Correspondence: Dr G Giamas, Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK. E-mail: [email protected] 1These authors contributed equally to this work. Received 21 January 2013; accepted 1 February 2013; published online 18 March 2013 Phosphatases and cancer J Stebbing et al 940 hypermethylation in primary tumours significantly correlated with PTPN13 was shown to interact with the cytosolic domain of tumour stage, indicating that PTPRO methylation may also be Fas,39 while Miyazaki et al.40 reported that overexpression of involved in invasion of ESCC.7 PTPN13 enhances sensitivity to Fas-mediated apoptosis. However, Yao et al.41 demonstrated that expression of PTPN13 in 470% of Gastric cancer colon cancers was related to resistance against Fas-mediated apoptosis in vivo and in vitro. These contradictory reports reveal Insertion of cagA-protein from Helicobacter pylori into the gastric that PTPN13 may possess dual role in colon carcinoma, either as epithelial cells specifically binds and activates PTPN11 oncopro- an oncogene or as a tumour suppressor depending on the cellular tein.9,10 Activated PTPN11 induces cell growth and motility,11 context in which it is studied. while deregulation of PTPN11 by cagA induces abnormal Lassmann et al.42 evaluated distinct genomic DNA alterations proliferation and migration of gastric epithelial cells that leads using array comparative genomic hybridization and identified to gastric carcinogenesis.12 Several studies detected aberrant DNA DNA amplification of PTPN1 in 22% of the CRC cases, with the methylation of PTPN6 gene in gastric carcinomas. H. pylori highest percentage of changes in chromosomal-positive infection led to a decrease in the methylation levels in PTPN6,13 tumours. PTPN1 has been responsible for the activation and inconsistent with a previous report.14 Yang et al.15 reported that elevation of Src kinase activity in six human epithelial colon PTPN1 gene was amplified in gastric cancer tissues. With regards cancer cell lines.43 to the clinicopathological characteristics, PTPN1 was associated Enhanced Src activity mediates signals and directs downstream with tumour metastasis and tumour-node-metastasis stage, activation of the Janus kinase–signal transducer and activator of implicating its involvement in the development of gastric transcription (JAK-STAT) pathway. Signal transducer and activator cancer.16 As suggested, PTPN1 inhibitors may also be useful in of transcription 3 (STAT3) has been shown to be activated in colon the treatment of gastric cancer.17 tumours and cell lines.44,45 Protein tyrosine phosphatase receptor- PTPN3 and PTPN4 are two closely related non-receptor tyrosine type T (PTPRT) and protein tyrosine phosphatase receptor-type D phosphatases that are expressed in human gastric cancer cells and (PTPRD) were shown to be able to regulate STAT3.46,47 tissue specimens.18 PTPN3 dephosphorylates and cooperates with As aforementioned, the mutation screen established that PTPRT p38g, to form a complex that may increase Ras oncogenesis was the most frequently mutated PTP in colorectal carcinomas. through post synaptic density protein (PDZ)-mediated direct Zhang et al.46 demonstrated that PTPRT specifically regulates binding.19 The phosphatase activity of PTPN4 has been implicated phosphorylation of STAT3-Tyr 705 in CRC. Overexpression of PTPRT in the regulation of cytoskeletal events.20 Overexpression of activity inhibited cell growth, suggesting a tumour-suppressor PTPN4 in COS-7 (cells being CV-1 (simian) in Origin) cells role.27 In addition, paxillin, a direct substrate of PTPRT, can be decreased colony formation, inhibited cell growth and dephosphorylated at Tyr88, which is involved in cell–cell adhesion. decreased saturation density of these cells.21 Mutated PTPRT could promote CRC tumourigenesis and cell Wu et al.22 applied a reverse transcriptase–PCR-based protein migration, while studies demonstrated the development of colon tyrosine phosphatase (PTP) profiling approach to study PTP tumours in PTPRT knockout mice.48 It has been shown that PTPRD is expression in human gastric cancer samples and identified frequently mutated in colon cancer.47,49 Mutations in PTPRD 16 PTPs in the cancer tissues; only 6 of them (PTPN4, PTPRB, abrogate its ability to regulate STAT3, and loss of PTPRD function PTPRH, PTPRJ, PRPRN and PTPRZ) were expressed in gastric cancer promotes cancer progression.50 tissue, while protein tyrosine phosphatase receptor type A (PTPRA) The role of PTPRA in CRC is poorly understood. PTPRA mRNA expression was significantly high in cancer tissues. The role of levels were found to be increased 70% in late stage (Dukes’ D) PTPRA) in gastric cancer might be linked to its biological role in colorectal tumours compared with adjacent normal colon integrin signalling, cell adhesion and activating the SRC family mucosa.51 Interestingly, overexpression of PTPRA increases tyrosine kinases.23–25 Reduced protein tyrosine phosphatase substrate adhesion25 and stromal invasion,52 while its silencing receptor type G (PTPRG) expression was detected by IHC in suppresses anchorage-independent growth and induces gastric tumour,22 indicating that it might be a tumour-suppressor apoptosis in colon cancer cell lines.53 gene. In addition, differences in DNA methylation of PTPRG genes PTPRH is also abundantly expressed in human CRC specimens54 between primary tumour and metastatic lymph nodes of gastric and CRC cell lines.29 PTPRH-deficient mice had normal intestinal cancer was also observed.26 Until now, the detailed mechanisms tract, but loss of PTPRH inhibited tumourigenesis in mice with underlying PTPRG-mediated cell signalling are not described. heterozygous mutation of the adenomatous polyposis coli gene, In a mutational analysis study conducted by Wang et al.,27 suggesting that PTPRH has a role in promoting the intestinal protein tyrosine phosphatase receptor type T (PTPRT) was the tumourigenesis.55 most common mutated gene. Lee et al.28 also detected a splice- Another significant phosphatase that modulated JAK-STAT site mutation in PTPRT gene in 1 of 48 gastric carcinomas and pathway is the low molecular weight protein tyrosine phospha- suggested that PTPRT phosphatase domain mutation may not tases (LMW-PTP). Malentacchi et al.56 observed an increase in the have a role in the development of human cancers. expression of LMW-PTP mRNA and protein levels in colon tumour Finally, various reports have demonstrated overexpression of samples; clinically, overexpression of LMW-PTP is generally protein tyrosine phosphatase receptor type H (PTPRH),29 Dual- associated with a proliferative phenotype and poor prognosis.57 specificity phosphatase 1 (DUSP1)30 and phosphatase of Here, overexpression of PRL-3 in primary colorectal tumours is regenerating liver (PRL-3)31–35 in human gastric cancer, while associated with tumour aggressiveness.58,59 Jiang et al.60 have Ooki et al.36 showed that PRL-3 genomic amplification was shown that the loss of transforming growth factor-b (TGF-b) associated with advanced stage. signalling leads to upregulation of PRL-3 expression and activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) Colorectal cancer pathway, which can promote epithelial–mesenchymal transition.61 A systemic mutational analysis of the tyrosine phosphatome in Further on, PTEN was downregulated by PRL-3 as shown by human colorectal cancer (CRC) has identified 83 somatic muta- protein expression and IHC.62–64 tions in PTPRF, PTPRG, PTPRT, PTPN3, PTPN13 and PTPN14 genes.27 Moreover, DUSP1 is overexpressed in colon tumours;65 Similarly, frameshift mutations have been depicted in Montagut et al.66 suggested DUSP1 as a potential biomarker of PTPRA, PTPRS, PTPN5, PTPN13, PTPN21 and PTPN23,37 while response to cetuximab in metastatic CRC patients. hypermethylation of PTPRO was showing microsatellite Finally, Ruivenkamp et al.67 demonstrated that frequent instability in colorectal tumours.38 deletion of the PTPRJ gene occurs in large percentage of

Oncogene (2014) 939 – 953 & 2014 Macmillan Publishers Limited Phosphatases and cancer J Stebbing et al 941 sporadic colorectal tumours and also found loss of heterozygosity regulation of CDC25B induces a G2/M arrest and subsequent at the PRPRJ locus in the sample of human CRC.62 apoptosis with a concomitant reduction of the 14-3-3 protein. Furthermore, inhibition of the CDC25B reduces the rate of renal 99 Pancreatic cancer cell migration and invasion. Cpd5 is a selective inhibitor of CDC25 phosphatases, which acts as an anti-neoplastic agent More than half of pancreatic ductal adenocarcinoma tissues 100 68–70 for RCC. exhibit increased PI3K and AKT expression. PH domain and Serine/threonine-protein phosphatase PP1-a catalytic subunit Leucine-rich repeat protein phosphatases (PHLPP) levels are (PPP1CA) is involved in pRb dephosphorylation and ceramide markedly reduced in human pancreatic ductal adenocarcinoma 101 71 accumulation induced by RAS. Its role has been investigated in that have elevated AKT phosphorylation. Studies have shown bladder cancer, as a potential marker for monitoring disease that PHLPP1 and PHLPP2 are able to terminate AKT signalling by progression. Assessment of PPP1CA levels in urine was performed directly dephosphorylating and inactivating AKT, resulting in great and correlated with standard cytology. Sensitivity of PPP1CA was suppression of tumour growth.72,73 68.8% and the specificity was 62.7% (Po0.001). A positive Although PTEN mutations are rarely found in pancreatic 74 correlation was found between bladder cancer grade and cancer, it is important to note that PTEN loss of function may sensitivity, while for grade 1 and grade 2 tumours, PPP1CA and result in decreased sensitivity to apoptotic stimuli that could other evaluated markers were even superior to cytology.102 promote cellular over-growth and tumourigenesis.75–77 Chow 78 PTPN21 stimulates the Src-EGF signalling axis, and its involve- et al. reported that TGF-b reduces PTEN expression and ment in actin cytoskeleton, cell adhesion and in regulating the enhances the motility of pancreatic cancer cells through stability and recycling of the epidermal growth factor receptor calcium-dependent PKCa. They also demonstrated that TGF-b (EGFR) has also been reported. PTPN21 is required for growth and downregulates PTEN via activation of nuclear factor (NF)-kB 79 motility of urothelial cancer cells in vitro, and its high expression in activity. Mutations and changes of expression levels of TGF-b human bladder cancer tissue correlates with advanced tumour and SMAD4 proteins could be observed in pancreatic cancer 80–82 stage and invasiveness. Therefore, PTPN21 represents a novel tissues. SMAD4 is a tumour suppressor able to mediate biomarker and possible therapeutic target for bladder cancer. signals from a family of TGF-b ligands and via phosphorylation of PTPN21 overexpression is thought to be an early step in urothelial receptor-activated SMADs (R-SMADs) proteins forming a trimeric cancer progression. In terms of expression in vivo, PTPN21 is complex. This complex translocates into the nucleus, binds to absent from the normal bladder tissue, hyperplastic urothelium specific DNA sequence and activates gene transcription.83 Protein 2 þ 2 þ and urothelial papilloma, whereas its expression gradually phosphatase, Mg /Mn dependent, 1A (PPM1A/PP2Ca) was increases from low grade to high grade urothelial carcinoma.103 identified as a phosphatase that dephosphorylates the SXS motif 84 In a study in clear cell RCC (ccRCC), which originates from of R-SMADs and terminates TGF-b signalling. proximal tubular tissue, microsatellite alternations at chromosome DUSP6 is a cytoplasmic DUSP that negatively regulates 9p23-22 (D9S168) were more common at late stage renal cancer members of the mitogen-activated protein (MAP) kinase super- and associated with poor survival. The D9S168 alteration was family (MAPK/ERK (extracellular signal–regulated kinase), SAPK associated with low expression of protein tyrosine phosphatase (stress-activated protein kinase)/JNK (c-Jun N-terminal kinase), receptor delta (PTPRD), while IHC analysis revealed downregula- p38), which are associated with cellular proliferation and differ- 85 tion of PTPRD expression in ccRCC, suggesting it as a potential entiation. DUSP6 dephosphorylates the active form of ERK2, which 104 86 tumour suppressor. is constitutively expressed in pancreatic cancer cells. Moreover, The PTEN gene is important for the growth suppression of RCC, DUSP6 was reduced in invasive pancreatic carcinoma86 and was 87,88 by inhibiting cell proliferation. In renal carcinoma cell lines and missinginthemajorityofcultured pancreatic cancer cells. primary RCC, the frequency of loss of flanking markers around Finally, NF-kB pathway has also been implicated in pancreatic PTEN is 20–43%, and somatic intragenic mutations are less cancer.89 Based on the classical NF-kB pathway cascade, the frequent (o17%). However, the rate of PTEN inactivation at the phosphorylated IKK (IkB kinase) can further phosphorylate IkB, an protein level may be more frequent than that identified at the inhibitory subunit of the NF-kB that is proteolytically degraded 105 90 genetic level. A tissue microarray analysing 440 RCC specimens upon phosphorylation. Protein phosphatase 2A (PP2A) is 106 91 revealed that PTEN expression is typically decreased in RCC, and required for signal-dependent activation of IKK. Inhibition of represents an early step in renal cell carcinogenesis. A negative PP2A triggers apoptosis in pancreatic cancer cell line through 92 93 correlation between pAKT and PTEN was found in primary RCC. constant activation of the NF-kB pathway. Li et al. also In terms of cellular distribution, PTEN was weaker at the suggested that treatment with cantharidin selectively inhibits cytoplasmic level and stronger in the nucleus in RCC compared PP2A and suppresses the growth of PANC-1 cells when c-Jun with normal renal parenchyma. Multivariate analyses revealed that N-terminal kinase pathway is over-activated. altered expression of PTEN was associated with adverse patient outcome.107 However, interestingly in patient samples with invasive muscular bladder cancer, PTEN was found to be located GENITO-URINARY TUMOURS in the cell cytoplasm and a positive correlation between PTEN and Renal cell and bladder cancer pAKT was observed.108 In addition, lower PTEN expression was Alkaline phosphatases (ALPL) are a group of tissue-specific and found in patients who died of metastases, within 5 years after tissue non-specific (TNAP) enzymes that have been previously surgery, compared with long-term survivors, indicating a critical implicated in suppressing meningiomas.94 However, the role of PTEN in RCC progression. In particular, the pro-metastatic relationship between ALPL levels and kidney cancer has not effects upon PTEN loss in RCC are achieved through Shc.109 been established. The kidney expresses ALPL, which is used as a PTEN attenuation also mediates resistance to cisplatin- marker for organ function in patients’ dialysis.95 High serum levels induced apoptosis, through increasing levels of the cyclin kinase of ALPL have been associated with paraneoplastic syndrome, inhibitor p21.110 as observed in 77 out of 365 patients with stage II–IV renal cell In primary bladder cancers, loss of PTEN heterozygosity is seen carcinoma (RCC), decreasing the 5-year survival to 35.7%.96 ALPL is in 23% of cases. Several portions of the gene were found deleted, also used as a predictive marker for bone metastases, which is a namely that containing potential tyrosine and serine phosphory- common occurrence in patients with kidney and bladder cancer.97 lation sites. Missense mutations in exon 1 and exon 2, which may CDC25 phosphatases are frequently overexpressed in various inactivate the phosphatase activity of the PTEN gene, were malignancies, including RCC.98 In renal cancer cells, down- detected in bladder cancer cell lines derived from advanced stage

& 2014 Macmillan Publishers Limited Oncogene (2014) 939 – 953 Phosphatases and cancer J Stebbing et al 942 bladder cancers and were absent from a cell line derived from a inhibition reserved prostate intraepithelial neoplasia through the lower stage cancer. However, in vivo analysis in 33 bladder cancer modulation of apoptosis and HIF-1 related pathways.129 Inhibiting specimens, including the 25 T3/T4 bladder carcinomas, failed to PDK1, which activates AKT and S6K, prevented the development replicate in vitro findings. Only 8% of the primary bladder cancer of prostate adenocarcinoma induced by PTEN heterozygous in specimens are thought to harbour a mutation or homozygous mice.130 It is now clear that tumours harbouring PTEN loss are deletion in PTEN, raising the possibility that another gene in close highly dependent on PI3K/AKT signal for survival and proliferation. proximity to PTEN is the actual primary target of inactivation.111 In Meanwhile, inhibition of these kinases can converse the effects of invasive bladder cancer, loss of PTEN in combination with altered PTEN loss.131 Therefore, pharmacological targeting PI3K/AKT and p53 has adverse consequences and serves to identify a subgroup of mTOR kinases have provided potential therapeutic importance in patients with particularly aggressive disease, which are candidates for PTEN-null cancers, including PCa. Indeed, several molecules, including mammalian target of rapamycin (mTOR) inhibitors as a therapeutic PI3K inhibitor (XL147), AKT inhibitor (perifosine) and mTOR inhibitors strategy.112 Finally, a recent mouse study found that PTEN deletion (CCI-779 and RAD001), are under clinical development.132 only influenced urothelial morphology when coupled with a deletion Furthermore, PTEN loss was shown to have an important role in of liver kinase B1 (LKB1), a tumour suppressor acting through the survival crosstalk between PI3K/AKT and androgen receptor tuberous sclerosis protein 1 (TSC1).113 (AR) in PCa progression. Upon acute androgen ablation in human Cyclin-dependent kinase-associated protein phosphatase (KAP) PCa cell line LNCaP, PTEN inactivation displayed increased activity is expressed at the G1/S transition of the cell cycle and forms a of the PI3K/AKT axis, indicating a possible compensating complex with cyclin-dependent kinase 2 (CDK2). KAP is over- phenomenon across PI3K/AKT and AR signalling.133,134 PCas with expressed in RCC, while a correlation with higher histological PTEN null relapsed after androgen withdrawal and enjoyed the grade has been shown.114 KAP promotes growth of RCC and capability of growth in the absence of androgen. Moreover, global confers resistance to anti-tumour necrosis factor-a-induced analysis of genomic alterations elicited by homozygous PTEN apoptosis by preventing caspase-3 activation. Furthermore, deletion identified genes associated with cancer metastasis.135 HEK293 cells overexpressing KAP have a greater ability of cell In addition, it has been reported that PTEN can suppress the invasion. In vivo xenograft models confirmed that KAP induces transcriptional activity of AR and cell proliferation induced by tumourigenicity, with significantly larger xenograft tumours androgen as well as prostate-specific antigen, whereas androgens arising in nude mice inoculated with KAP over-expressing cells. prevented PCa cells from PTEN-dependent apoptosis in the DUSP1 expression in renal cancer cells contributed to cell presence of AR.136 Similar evidence described that PTEN can survival by attenuating the apoptosis-inducing signal cascade via directly interact with AR resulting in an inhibition of the AR nuclear JNK. DUSP1 is upregulated at the mRNA and at the protein level in translocation and an increase of the AR degradation in a PI3K/AKT- low-grade bladder cancers, and its expression is inversely independent manner, while in PTEN-null context both proportional to tumour grade, suggesting its relevance in the AR expression and activity were elevated compared with wild- early stages of bladder cancer development.115 DUSP9 expression type MEFs.137 Collectively, PTEN loss may lead to a gain-of- correlates with the onset of kidney carcinoma, where it is function of AR in both PI3K/AKT-dependent and -independent downregulated at both the mRNA and at the protein level. environment. Coordinately, loss of PTEN and intensified AR may Patients with tumours exhibiting low DUSP9 expression had contribute to tumourigenesis and androgen refractory PCa. significantly worse overall survival, indicating that DUSP9 Pro-apoptotic protein Par-4 was shown to be essential for PTEN- expression has an independent predictive value.116 dependent apoptosis, while AKT can directly bind to Par-4 and HER-2-positive bladder cancers also exist and carry an adverse inhibit its activity through phosphorylation resulting in the survival prognosis. Suppression of interferon-g is often used as a of PCa cells.138 Recent studies demonstrated that Par-4 therapeutic approach in bladder cancer patients. This treatment inactivation associates with PTEN loss in a high percentage of is probably less effective in HER-2 overexpressing/amplified human prostate carcinomas. Similar to PTEN-heterozygous mice, tumours due to upregulated Src homology 2-containing PTPN11 Par-4-null mice only developed benign prostate lesions, whereas signalling. A dysfunction in PTPN11 regulation can cause abnormal simultaneous Par-4 loss and PTEN haploinsufficiency caused cell growth and induce different kinds of cancers.117 PTPN11 is invasive PCa in mice through activating AKT signalling as well as mainly expressed in the collecting duct system and in distal NF-kB pathway.139 tubules and hardly in glomeruli and proximal tubules. Its Protein phosphatase 1 (PP1) and PP2A are two major classes of abundance was evident in rare renal tumours, such as serine/threonine protein phosphatases involved in many different chromophobe RCC or oncocytoma.118 cellular processes, including survival, cell cycle and apoptosis, Finally, the inhibitor of apoptosis stimulatory protein phospha- through dephosphorylation of key regulators, such as PKA, AKT, tase (iASPP) is a key inhibitor of p53. iASPP is important for PKC and glycogen synthase kinase 3.140,141 PP2A comprises of bladder cancer cell proliferation,119 where it has been shown that several subunits: scaffolding, catalytic and regulatory. Each iASPP knock down inhibits cell growth and colony formation.120 subunits of PP2A exists in at least two isoforms.142,143 PPP2CA levels were found decreased in majority of androgen-independent PCa cell lines and in cancer lesions as compared with the adjacent Prostate cancer normal/benign tumour tissues.144 PPP2R2A, a potential tumour- PTEN mutations were firstly identified in multiple advanced suppressor gene, was found commonly deleted among PCa with cancers, including prostate cancer (PCa), leading to its potential homozygous deletions and no significant association between role as a tumour-suppressor gene.121,122 Shortly, different groups common single nucleotide polymorphisms of PPP2R2A and confirmed that PTEN inactivation was frequently shown in sporadic PCa. These findings suggested that it may have an prostate cell lines, xenografts as well as primary PCa.123–126 important role in PCa tumourigenesis on somatic levels.145 In PCa, Homozygous deletion of PTEN in the prostate epithelium resulted caveolin-1 was shown to bind to and inhibit PP1 and PP2A in malignant prostate carcinoma displaying its association with resulting in AKT activity enhancement, indicating an important cancer progression.127 Biological function studies showed that by interplay involving both the phosphatases in tumourigenesis.146 dephosphorylation of PIP3 to PIP2, PTEN tumour suppressor acts as Recent studies showed that PP1 can regulate AR protein stability a vital negative regulator of the PI3K/AKT/mTOR pathways and cellular localization via dephosphorylation of Ser-650.147 affecting many aspects of cellular activity, including growth and 2,4,30,50 tetramethoxystilbene, a synthetic trans-stilbene analogue, survival, whereas loss of PTEN leads to activation of these was able to induce PP2A activation leading to inhibition of AKT. signalling cascades.77,128 In AKT-dependent mouse model, mTOR This, in turn, stimulated expression of cell-cycle inhibitor p27(kip1)

Oncogene (2014) 939 – 953 & 2014 Macmillan Publishers Limited Phosphatases and cancer J Stebbing et al 943 in PC-3 cells.148 A failed recruitment of PP2A-Ba by TGF-b type 1 with low grade and type-II with clear-cell or serous morphology receptor was suggested to be partly responsible for TGF-b and high grade.165–167 Currently, endocrine and chemotherapy are abundance in malignant prostate cells.149 Moreover, PP2A being used to treat type-I EC.168 Although most clinical trials and activity was decreased in androgen-independent PCa cells (C4-2) treatment regimens do not stratify patients according to type, compared with androgen-dependent LNCaP cells, whereas research at molecular level have identified distinct genetic inhibition of PP2A enabled LNCaP cells to grow in an androgen- alterations and signalling pathways between the two types. For deprived condition.150 Sodium selenate, a specific selenium- example, type I cancer frequently has deregulated PI3K/PTEN/AKT containing compound, was identified as a PP2A activator, which pathway and loss of PTEN function while type-II has alterations in significantly augmented the activityofPP2A,therebyinhibitingVEGF P53 and/or P16 pathways along with overexpression and (vascular endothelial growth factor)-induced growth and vessel amplification of HER2. branching of endothelial cells and obstructing tumour neovasculari- PP2A is a well-known tumour suppressorthatinhibitsRAF-MEK-ERK zation. This anti-angiogenisis effect via PP2A allowed it into a phase 1 pathway by inhibiting activity of ERK and RAF besides inhibiting study in patients with castration-resistant PCa and results showed a the downstream signalling of RAS pathway via dephosphorylation similar effect to other anti-angiogenic agents.151,152 and inhibition of c-Myc, RALA and AKT. Depending on the type of The cell division cycle 25 (CDC25) families are DUSPs function- cancer, this function of PP2A has been shown to be mediated by ing in activation of CDKs, which in turn modulate cell-cycle regulatory b subunits.169 On the contrary, somatic missense progression. In mammalian cells, three isoforms have been mutations in PPP2R1A, which encodes the a-isoform of the PP2A identified: CDC25A, CDC25B and CDC25C.153 CDC25A and scaffolding subunit, were demonstrated in high-grade serous CDC25B were shown to be overexpressed in human PCa tissues endometrial tumours.170 and high CDC25B level was associated with high Gleason scores Constitutive activation of MAPK pathway is known to have an and aggressiveness in PCa.154,155 These two different studies also important role in EC and as DUSP6 can negatively regulate ERK2, demonstrated that CDC25A can suppress androgen-responsive Chiappinelli et al.171 studied its methylation status in EC. They promoter via physically interacting with AR, whereas CDC25B can identified that silencing of DUSP6 is uncommon and unlikely to function as a coactivator of an AR in a hormone-dependent cause activation of MAPK pathway in EC. On the other hand, manner in LNCaP. Similarly, CDC25C expression was elevated in LMW-PTP was studied and a significant association was identified PCa in comparison with normal prostate tissues and its spliced in low-grade EC with genotypes carrying the C allele along with isoform was also found to be correlated with increased growth high concentration of S isoform.172 in PCa.156 Theaflavin, a black tea polyphenol, can cause G2/M Finally, Allard et al.173 studied the role of phosphatases in phase arrest in PC-cells by inducing cyclin kinase inhibitor p21 determining racial inequality in EC. Using microarray, they (waf1/cip1) and inhibiting CDC25C and cyclin B.157 Taken identified phosphoserine phosphatase (PSPH), which is essential together, several studies have shown that CDC25 family for the synthesis of L-serine, and designated phosphor-serine phosphatases are important players in PCa progression and may phosphatase-like (PSPHL) as the most overexpressed genes in provide potential therapeutic targets in PCa. EC in African-Americans when compared with Caucasians. SHP1, an SH2 domain-containing protein tyrosine phosphatase, was detected in normal prostate, benign prostate hyperplasia, prostate epithelial cells and well-differentiated adenocarcinoma, Cervical cancer whereas diminished SHP1 expression was observed in malignant The role of PP1 in tumour metastasis was studied by knock down prostate tissue and poorly differentiated advanced PCa.158–161 of PP1 and its regulator NIPP1 in HeLa cells. Knock down of PP1 Moreover, SHP1 overexpression decreased PC-3 cell prevented migration of HeLa cells by inhibiting Cdc42 signalling proliferation.159 Tassidis et al.161 demonstrated that the pathway.174 Zeng et al.175 identified protein phosphatase 1 expression of SHP1 mRNA and protein in two human PCa cell inhibitor 5 (IPP5) as a tumour suppressor in cervical cancer (CC); lines, LNCaP and PC-3, were at different levels. In this study, overexpression of mutant IPP5 in HeLa cells caused G2/M arrest silencing SHP1 in LNCap, which expresses high amount of both in vitro and in vivo via inhibition of ERK activation. endogenous SHP1 protein, exhibited an increase in cellular Furthermore, Protein phosphatase 1, regulatory subunit 7 was proliferation and cyclin D1. By contrast, in PC-3 cells, with low shown to be significantly upregulated in metastatic CC patient endogenous level of SHP-1 expression, overexpression of SHP-1 samples after radiotherapy.176 Moreover, hSHIP, a human resulted in a decrease in proliferation and cyclin D1. A recent SH2-containing inositol-5-phosphatase, has also been shown to study showed that depletion of SHP1 in PC-3 cells caused inhibit growth and act as a tumour suppressor in CC. In vitro and G1 phase cell-cycle arrest by increasing p27 protein stability, due in vivo studies by He et al.177 have shown that stable to its capability of regulating PI3K/AKT pathway and CDK2 activity. overexpression of hSHIP induces S-phase arrest along with This indicated that SHP1 may have a role in the regulation of downregulation of AKT1/2 expression and phosphorylation, cell-cycle progression.162 thereby inhibiting proliferation of CC HeLa cells. Taken together, SHP2, an SH2 domain-containing protein tyrosine phosphatase PP1 and its regulatory subunits along with hSHIP have an sharing homology with SHP-1, is also expressed in PCa cell lines, important role in progression and therapeutic response in CC including PC-3, DU145, LNCaP and LNCap-IL6 þ (interleukin-6 þ ) and can prove to be new therapeutic targets. as well as patient specimens with PCa. SHP2 staining from DUSP3 is known to dephosphorylate ERK1/2 and JNK1/2 MAPK 122 patients showed that low cytoplasm intensity associated inversely kinases, which are key regulators of cellular differentiation, with prostate volume while staining in the nucleus was positively proliferation and apoptosis. In CC, knockdown of DUSP3 inhibited correlated with extracapsular extension. This implicated that SHP-2 the growth of HeLa CC cells by increasing the expression of cyclin- ablation in the cytoplasm correlated with enhanced tumour dependent kinase inhibitor, p21 and inhibiting G1-S and G2-M growth.163 However, other studies reported that SHP2 may act as a cell-cycle transition.178 This in vitro study was further supported by proto-oncogene product by increasing Ras-MAPK signalling.164 detection of increased expression and nuclear localization of DUSP3 in cervix cancer cell lines when compared with normal keratinocytes as well as in HPV (human papillomavirus)-positive GYNAECOLOGICAL TUMOURS cell lines when compared with HPV-negative cell lines. Endometrial cancer Furthermore, increased expression was identified in primary There are two main types of endometrial cancer (EC) namely type-I, cervix cancer biopsies, including squamous cell carcinomas of which is oestrogen receptor and progesterone receptor positive unterine cervix and squamous intra epithelial lesions indicating

& 2014 Macmillan Publishers Limited Oncogene (2014) 939 – 953 Phosphatases and cancer J Stebbing et al 944 potential use of DUSP3 as a new marker for progression of CC and grade, histotype, stage and residual tumour after surgery, thereby as a new target for anticancer therapy.179 Small-molecule indicating potential role of these phosphatases to be used as inhibitors for DUSP3 have been developed that can inhibit prognostic factors.201 enzymatic activity of DUSP3 at nanomolar concentrations while Using northern blots and immunoblotting, Mok et al.202 have inhibiting the proliferation of cervix cancer cell lines without shown that PTPN6 was overexpressed in seven of the eight affecting proliferation of primary normal keratinocytes.180 ovarian epithelial carcinoma cell lines both at RNA and protein PP2B or serine/threonine phosphatase calcineurin was shown to level along with overexpression in invasive ovarian epithelial promote CC cell proliferation by directly interacting and enhan- cancer tissues. cing c-Jun protein stability and activity. This was confirmed in Cisplatin is one of the most widely used drugs for treating OC. cervical tissue samples that showed decreased phosphorylation Sensitivity to cisplatin is known to be partly mediated by of c-Jun and enhanced total PP2B and c-Jun expression.181 activation of p53 by checkpoint kinase 1 (CHK1). Protein By contrast, PP2B was shown to be downregulated in malignant phosphatase magnesium-dependent 1 (PPMD1) is known to squamous carcinomas.182 This inconsistency might be due to the deactivate p53 and Chk1 via dephosphorylation. Using cisplatin- small number of samples used in both the studies and requires resistant cell lines, Ali et al.203 showed knock down of PPMD1 can further investigation. On the other hand, no mutations were re-sensitize resistant cells to cisplatin by activating P53 and CHK1. identified in PPP2R1B gene, which encodes the beta isoforms of Moreover, PPM1D was shown to be highly expressed at mRNA the subunit A of the PP2A between normal and cancer cell level in ovarian clear-cell carcinoma cell lines with amplification at lines.183 17q23.2 and was amplified in 10% of primary clear-cell Expression of SHP-2 tyrosine phosphatase, was negatively carcinomas.204 The role of protein phosphatases in cisplatin associated with interferon-b expression in CC while its silencing sensitivity was also studied by Bansal et al.205 and they identified inhibited growth of SiHa CC cell line by inducing expression of that patients with incomplete response to cisplatin had twofold interferon-b.184 Other phosphatases that can either inhibit or lower PP2C levels when compared with those with complete promote CC include hSHIP, a human SH2-containing inositol-5- response. This was confirmed by western blotting in platinum- phosphatase and DUSP-3, respectively.177,179,180 resistant OC cells. Moreover, genome-wide expression profiling of Cancerous inhibitor of protein phosphatase 2A (CIP2A) was SK-OV-3 OC cells identified two regulatory subunits of PP2A as key shown to be overexpressed in CC when compared with normal mediators of sensitivity to cisplatin and knock down of each tissue by IHC and reverse transcriptase–PCR. More importantly, subunit by RNA interference made OC cells more responsive to papillomavirus 16 E7 oncoprotein directly upregulated CIP2A cisplatin.206 expression, which could enhance proliferation and growth of CC Polato et al.207 studied the role of PRL-3 in OC and expression of cells by modulating c-Myc expression.185 PRL-3 mRNA was found to be higher in stage III OC samples when Finally, mutation and loss of PTEN has also been shown to drive compared with stage I samples, and by using small interfering tumourigenesis here,186,187 as previously described. RNA, PRL-3 was shown to be important for growth of OC cells in vitro.207,208 Moreover, PRL-3 regulated migration and invasion of OC cells by interacting with integrin a1, inhibiting Ovarian cancer phosphorylation of integrin b1 and enhancing the downstream Inactivation of PTEN by genetic mutation is well known in ovarian phosphorylation of Erk1/2.209 In vivo mice studies have shown that cancer (OC).188 Several in vitro studies have shown that PTEN can monoclonal antibodies against PRL-3 can prevent both tumour regulate growth, invasion, migration and resistance to growth and metastasis of OC cells making it a potential target for chemotherapy in OC.189–193 Interestingly, PP2A has been shown therapy in OC.210 to regulate PTEN; inhibition of PP2A decreased the expression of Finally, Tanyi et al.211 identified decreased mRNA expression of PTEN and enhanced phosphorylation of PTEN and AKT, causing phosphatidic acid phosphatase type 2A (PPAP2A, LPP-1) in OC, increased migration/invasion of OC in fibrillar collagen, indicating which is known to degrade lysophosphatidic acid that can PP2A as a tumour suppressor in OC. This was further supported by promote tumour growth and metastasis. detection of decreased expression and activity of PP2A in OC tissue.194 Expression of CIP2A, studied in 562 serous OC patients by IHC, showed strong cytoplasmic staining in 40% of the samples and OTHER TUMOURS was associated with high grade, advanced stage and poor Lung cancer outcome.195 On the other hand, inhibition of PP2A was essential Several phosphatase (PTPases) have been identified to have a role for the apoptosis induced by doxorubicin,196 and translocation of in this malignancy. Omerovic et al.212 performed a phosphatome PP2A to plasma membrane was essential for gonadotropin- RNAi screen in A549 lung cancer cells and ranked their effects on releasing hormone (GnRH) antagonist cetrorelix-induced phosphorylation of AKT-Ser473. Although, PTEN appeared to be apoptosis in GnRH-responsive OC cells.197 the main factor involved in inhibiting the oncogenic K-Ras, A study by Manzano et al.198 evaluating the expression of other phosphatases have been identified with similar 68 phosphatases in ovarian epithelial and cancer cell lines potencies, including protein tyrosine phosphatase non-receptor identified a 10–25-fold higher expression of DUSP1 in normal type 2 (PTPN2) and protein tyrosine phosphatase non-receptor compared with malignant OC cell lines. This was confirmed by IHC type J (PTPRJ).212 PTEN protein expression was reduced or lost in staining in normal and OC specimens and was shown to be a 74% of lung tumours, with loss occurring more often in well to critical factor in the progression of cancer. moderately differentiated tumours. In non-small-cell lung PTPN13 was found to be increased both at RNA and protein carcinoma (NSCLC), loss of PTEN protein expression occurs level in Fas-resistant OC cell lines as well as in OC patient samples frequently, although the mechanism responsible for loss is not studied using tissue microarray.199 Knock down of PTPN13 using clearly attributable to deletion or epigenetic silencing. PTEN loss small interfering RNA enhanced the sensitivity of SKOV3 cells to may also be a favourable prognostic marker, although further carboplatin, indicating that it can have a key role in carboplatin studies are needed to confirm this finding.213 Scrima et al.214 have resistance.200 suggested protein tyrosine phosphatase non-receptor type 13 In 106 OC patient samples, cell-cycle-related phosphatases, (PTPN13) as candidate tumour-suppressor gene in NSCLC. This CDC25A and CDC25B, were found to be commonly expressed and gene is frequently inactivated in NSCLC through somatic mutation were associated with poor prognosis independent of tumour (approximately 8%) or due to loss of protein expression

Oncogene (2014) 939 – 953 & 2014 Macmillan Publishers Limited Phosphatases and cancer J Stebbing et al 945 (approximately 73%); PTPN13 negatively regulates anchorage- PTPN13 is sufficient to block the IRS-1 (insulin receptor substrate dependent and anchorage-independent growth of NSCLC cell 1)/PI3K/MAPK pathway.226 In addition, overexpression of PTPN13 lines in vitro.214 in combination with anti-oestrogen treatment increased apoptotic The CDC25 phosphatases are known to have an important role cell death by the reduction of IGF-1 (insulin-like growth factor 1) in cancer cell growth. Increased expression of CDC25B has been induced IRS-1 and AKT phosphorylation.227 PTPN13 can also reported in tumours of different tissue origins, including NSCLC. inhibit tumour aggressiveness via the direct dephopshporylation Analysis of primary tumours and corresponding healthy lung of Src at Y419,224 which is upregulated in tamoxifen-resistant tissues from 177 patients with NSCLC revealed an overexpression ER-positive breast cancer patients.228 New therapeutic routes using of CDC25B in 45.76% of the samples. Moreover, high expression of tamoxifen and SRC inhibitors are currently being examined.229,230 CDC25B correlated with positive expression of endothelin and Loss of functional PTEN has been described in primary and with the number of intratumoural microvessels. Statistical analysis metastatic breast tumours,231,232 resulting in hyperactivation of of survival data revealed that elevated CDC25B expression was the PI3K pathway and an increase in cell proliferation.233 significantly associated with shorter disease-free and overall Downregulation of PTEN activity and activation of the PI3K survival, suggesting that CDC25B might have an important role signalling pathway is associated with resistance to anti-oestrogen in the angiogenic process and in determining the prognosis of therapy.234 Screening for PTEN mutations may identify BC patients patients with NSCLC.215 who may benefit from treatment with AKT inhibitors. In this regard, Another protein known to have a role here is the DUSP1. It has BC cell lines with PTEN mutations were recently described to have been shown that downregulation of DUSP1 induced changes in increased sensitivity to the novel AKT inhibitor MK-2206.235 the expression levels of genes involved in specific biological Several other PTPs have a tumour-suppressor function in BC. pathways, including angiogenesis, MAP kinase phosphatase PTPN12 has been shown to act as a potent tumour suppressor in activity, cell–cell signalling, growth factor and tyrosine-kinase triple-negative breast cancer cells and is more frequently receptor activity. Changes in the expression of some of these inactivated in this BC subtype. Genetically silencing PTPN12 genes were due to modulation of c-Jun-N-terminal kinase and/or induces transformation and disrupts acinar formation in mammary p38 activity by DUSP1. Another report showed that silencing of epithelial cells.236 Levels of cytoplasmic protein tyrosine DUSP1 inhibits invasion and metastasis in NSCLC tumour.216 phosphatase non-receptor type 9 (PTPN9) inversely correlate Moreover, Chitale et al.217 examined 199 lung adenocarcinomas with STAT3 in BC tissue.237 PTPN9 has been reported to inactivate by integrating genome-wide data on copy number alterations and STAT3 following EGFR dephosphorylation in breast cancer cells,238 gene expression and revealed that non-random patterns of copy suggesting that PTPN9 may have a critical role in BC development. number alterations are linked to EGFR and KRAS mutation status. A number of DUSPs are dysregulated in BC. The majority of They also discovered a striking association of EGFR mutations with breast carcinomas, including both poorly differentiated and under-expression of DUSP4, which is involved in negative metastatic stage diseases, express higher levels of DUSP1 feedback control of EGFR signalling. Clinically, DUSP4 loss has a compared with normal breast tissue.65,239 Studies suggest that significant impact on overall survival, further supporting its inhibition of DUSP1 may be an effective therapeutic target against biological significance in lung adenocarcinomas. chemoresistance in BC patients. Increased expression of DUSP1 DUSP4 loss also associates with p16/CDKN2A deletion and has been shown to correlate with decreased JNK activity.239 defines a distinct clinical subset of lung cancer patients.217 Overexpression of DUSP1 in BC cell lines treated with Another phosphatase that seems to have a role in tumourigen- chemotherapeutic agents, which target the JNK pathway, esis is the protein tyrosine phosphatase non-receptor type 12 protects against apoptosis. Conversely, genetic or chemical (PTPN12), by regulating cell adhesion and migration. However, the silencing of DUSP1 enhances sensitivity to chemotherapeutics mechanism by which PTPN12 is regulated in response to agents,240 indicating that combination therapies that target this oncogenic signalling is unclear. Zheng et al.218 have shown that enzyme may be effective in the treatment of BC. Ras induces ERK1/2-dependent phosphorylation of PTPN12 at DUSP3, DUSP4 and DUSP5 also negatively regulate ERK Ser-571, which recruits peptidylprolyl cis/trans isomerase, NIMA- signalling. DUSP4 upregulation has been described in interacting 1 (PIN1) to bind to PTPN12. Isomerization of the BC tumours.239 Deficiency of DUSP4 has been identified as a phosphorylated PTPN12 by PIN1 increases the interaction mechanism of neoadjuvant drug chemoresistance in breast between PTPN12 and focal adhesion kinase (FAK, PTK2), which cancer tumours. DUSP4 depletion is frequently found in leads to dephosphorylation of FAK-Tyr397 and the promotion of chemotherapy refractory tumours, which are associated with migration, invasion and metastasis of v-H-Ras-transformed cells.218 increased cell proliferation and basal-like BC status. Overexpression of DUSP4 either in breast cancer cell lines or in BC xenograft mouse models increased chemotherapy-induced Breast cancer apoptosis, whereas depletion reduced chemosensitivity.241 Upregulation of PTPN1 was first described in human breast cancer Upregulation of DUSP3 and DUSP5 has been reported in PMA (BC) cell lines overexpressing the neu oncogene.219 Wiener et al.220 (phorbol myristate acetate)-treated MCF-7 and BKBR3 breast reported a correlation between increased expression of PTPN1 cancer cell lines. Activation of the ERK1/2 pathway and and HER2 expression in human mammary tumours compared with accelerated growth arrest of BC cells has been observed normal breast tissue. Global deletion of PTPN1 either delayed or following silencing of either DUSP3 or DUSP5, and protected against mammary cancer in mice, depending on the overexpression of either phosphatase prevents growth inhibition HER2/Neu allele and mice strain used,221,222 suggesting that and cell migration.242 inhibition of PTPN1 may be a potential target for treating breast The novel phosphatase, VHZ (VH1-like (member Z)), encoded by cancer. Targeted PTPN1 silencing in the mammary epithelium of the DUSP23 gene, is also associated with BC and has been either established mouse tumours or in human BC cells xenografts identified in some invasive ductal and epithelia BC tumours. VHZ grown on HER2-positive mice has been shown to delay the early has been shown to localize to the centrosome and enhance G1/S onset of formation of mammary tumours.223 cell-cycle progession, suggesting that this enzyme may be a Recent studies indicate that PTPN13 may be an effective potential chemotherapeutic target.243 therapeutic target for the treatment of breast cancer. Lower levels All three CDC25 isoforms (CDC25A, CDC25B, CDC25C) can 153 of PTPN13 have been described in BC and metastatic tissue regulate G1/S and G2/M cell-cycle transition. CDC25A over- specimens224 and increased expression of PTPN13 is associated expression is associated with poor survival in BC patients.244–246 In with a favourable outcome in BC patients.225 Overexpression of addition, CDC25A 263C/T and -51C/G polymorphisms that are

& 2014 Macmillan Publishers Limited Oncogene (2014) 939 – 953 Phosphatases and cancer J Stebbing et al 946 associated with BC incidence and metastatic potential have been mesenchymal transition.259 High-throughput screening assays identified in BC patients, suggesting that CDC25A gene may be have recently identified a series of specific small molecule EYA2 candidate marker for earlier diagnosis and target for BC phosphatase inhibitors that may be useful for the development of therapy.247 Recent studies have demonstrated increased Fox1 future BC therapies.260 activity following CDC25A-indcued dephosphorylation of CDK2. Inhibition of CDC25A inhibits metastases in BC mouse models, suggesting that this phosphatase may be a potential target for Sarcomas advanced stages of the disease.248 CDC25B is overexpressed in Sarcomas are probably even more heterogenous than all the primary BC tumours,249 although expression levels do not always aforementioned tumour types.261 correlate with an aggressive phenotype.250 CDC25C splice variants PP2A has been identified in a protein array screen for interacting have been found to shift or be elevated in BC cell lines, particularly proteins with the Kaposi’s sarcoma-associated herpesvirus (KSHV) in cell lines with multi-drug resistance or those treated with sub- LANA protein, which functions in latently infected cells as an lethal levels of genotoxic agents,251,252 suggesting that CDC25C essential component of KSHV replication and dysregulated cell splicing may be an additional regulatory event involved in cellular growth. The subunits PP2A and PP2B, but not the catalytic subunit response to DNA damage in BC cells. PP2C, were found to associate with LANA, suggesting that PP2A The oncogene SRC3, which is overexpressed or amplified in the activity may be dysregulated in this sarcoma.262 majority of breast cancer tumours,253 is a target for PP1. PP1 can Alterations in PTEN expression have been described in several block proteasome-dependent turnover of SRC-3 by types of sarcoma. PTEN upregulation has been described in 80% dephosphorylation at Ser-101 and Ser-103, resulting in the of tissue samples from Kaposi’s sarcoma biopsies, with 58% stabilization of SRC-3.254 Increased expression of mutated PP2A expressing phosphorylated PTEN.263 PTEN losses and mutations at the active phosphatase site pY307 has been reported in are also a frequent occurrence in the malignant smooth muscle HER2/neu BC tumours, which significantly correlated with disease neoplasm, leiomyosarcoma.264–266 progression.255 Loss of PP2A activity in HER2/neu-positive BC cells SHP2 may be a promising therapeutic target for Kaposi’s resulted in apoptotic cell death mediated by p38 MAPK caspase-3 sarcoma. Constitutive activation of the viral G protein-coupled PARP activation,256 suggesting that this phosphatase may be a (vGPC) receptor, the Kaposi’s herpes sarcoma virus associated potential therapeutic target in BC. chemokine, has been shown to result in the phosphorylation of MCF-7 cells carry an amplified PPM1D/Wip-1 gene and over- SHP2.267 The vGPCR contains a bona fide immunoreceptor express PPM1D phosphatase protein. Silencing PPM1D has been tyrosine-based inhibitory motif that binds and constitutively reported to enhance doxorubicin-induced apoptosis due to activates Shp2.268 Moreover, SHP2 is required for vGPCR p53-mediated phosphorylation of Bax.257 activation of the MEK-ERK1/2 axis, the transcription factors AP-1 Overexpression of the Eyes Absent (EYA) family of proteins, and NF-kB and vGPCR-induced endothelial cell migration.267 which are essential co-activators of the Six1 family of homeobox PTPN13 is highly expressed in Ewing’s sarcoma cell lines and in transcription factors, have recently been reported to enhance the patient tumours, with higher expression levels in metastatic proliferartion, migration and invasiveness of BC cells.258 Silencing compared with primary tumours. PTPN13 has been found to of EYA2 in MCF-7 cells reverses the ability of Six1 to induce TGF-b associate with the aberrant transcription factor EWS-11 and is signalling and induce characteristics associated with epithelial– upregulated following overexpression of EWS-11.269

JAK/STAT pathway ERK pathway

PTPRJ PI3K/PKB/mTOR JNK pathway LMWPTP pathway

PTPN1 PTPRA PRL3

PTEN

LMWPTP

PTPRT DUSP3 LMWPTP DUSP3 DUSP6 DUSP6 PTPRJ PTPN13

cell survival apoptosis resistance cell differentiation angiogenesis

cell proliferation metastasis

Figure 1. Schematic overview of signalling pathways regulated by selected PTPs in cancer. Phosphatase effects on specific proteins are indicated by lines with dots and downstream signalling effects are indicated by lines with arrows. , Grb2, growth factor receptor-bound protein 2; MEK/MKK: mitogen-activated protein kinase kinases, PKB, protein kinase B; SOS, son of sevenless.

Oncogene (2014) 939 – 953 & 2014 Macmillan Publishers Limited Phosphatases and cancer J Stebbing et al 947 proliferation, differentiation, angiogenesis and metastasis. Thus Table 1. Alterations observed in phosphatases and resulting far, a large number of phosphatases has been associated with the malignancies development and progression of different types of cancer Gene Uniport Expression (Table 1). Further understanding and clarifying the involvement symbol KB and role of phosphatases in signal transduction is likely to be helpful in developing targeted drugs to be used alone or in PTEN P60484 Lung,213 oesophageal,1–3 pancreatic,74 combination with other therapeutics for cancer treatment. kidney,106 bladder,111 cervical,186,187 ovarian,188 breast,231,232 sarcoma,263 123–126 prostate CONFLICT OF INTEREST PTPN1 P18031 Gastric,15,271 colorectal,42 breast219 PTPN2 P17706 Lung212 The authors declare no conflict of interest. PTPN3 P26045 Gastric,18 colorectal27 PTPN4 P29074 Gastric18,22 PTPN6 P29350 Gastric,13 ovarian,202 prostate158–161 ACKNOWLEDGEMENTS 237 PTPN9 P43378 Breast We thank Aleksandra Filipovic for helping in editing the manuscript. JS and GG are 216 30 ,65,66 PTPN10 P28562 Lung, gastric, colorectal supported by grants from the National Institutes of Health Research, Imperial 115 198 65,239 bladder, ovarian, breast Biomedical Research Centre and Experimental Cancer Medicine Centre, Breast Cancer 9,10 118 184 PTPN11 Q06124 Gastric, kidney, cervical, Campaign, Cancer Research UK and Action Against Cancer. sarcoma,267 prostate163 PTPN12 Q05209 Lung,218 oesophageal,6 breast236 PTPN13 Q12923 Lung,214 colorectal,27,41 ovarian,199 breast,225 sarcoma269 REFERENCES PTPN14 Q15678 Colorectal27 1 Zhou YA, Zhang T, Zhao JB, Wang XP, Jiang T, Gu ZP et al. 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